Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT153922)

• DOT Name: Ketohexokinase (KHK)
• Synonyms: EC 2.7.1.3; Hepatic fructokinase
• Gene Name: KHK
• Related Disease: Essential fructosuria
• UniProt ID: KHK_HUMAN
• PDB ID: 2HLZ; 2HQQ; 2HW1; 3B3L; 3NBV; 3NBW; 3NC2; 3NC9; 3NCA; 3Q92; 3QA2; 3QAI; 3RO4; 5WBM; 5WBO; 5WBP; 5WBQ; 5WBR; 5WBZ; 6UL7; 6W0N; 6W0W; 6W0X; 6W0Y; 6W0Z; 8OME; 8OMF; 8UG1; 8UG3
• EC Number: 2.7.1.3
• Pfam ID: PF00294
• Sequence:
  MEEKQILCVGLVVLDVISLVDKYPKEDSEIRCLSQRWQRGGNASNSCTVLSLLGAPCAFM
  GSMAPGHVADFLVADFRRRGVDVSQVAWQSKGDTPSSCCIINNSNGNRTIVLHDTSLPDV
  SATDFEKVDLTQFKWIHIEGRNASEQVKMLQRIDAHNTRQPPEQKIRVSVEVEKPREELF
  QLFGYGDVVFVSKDVAKHLGFQSAEEALRGLYGRVRKGAVLVCAWAEEGADALGPDGKLL
  HSDAFPPPRVVDTLGAGDTFNASVIFSLSQGRSVQEALRFGCQVAGKKCGLQGFDGIV
• Function: Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.
• Tissue Specificity: Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Fructose catabolism (R-HSA-70350)
  Essential fructosuria (R-HSA-5657562)
• BioCyc Pathway: MetaCyc:HS06437-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Essential fructosuria	DISO0K23	Supportive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Ketohexokinase (KHK) decreases the response to substance of Afimoxifene.	[14]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ketohexokinase (KHK).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ketohexokinase (KHK).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ketohexokinase (KHK).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ketohexokinase (KHK).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ketohexokinase (KHK).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ketohexokinase (KHK).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ketohexokinase (KHK).	[3]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Ketohexokinase (KHK).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ketohexokinase (KHK).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ketohexokinase (KHK).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ketohexokinase (KHK).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ketohexokinase (KHK).	[12]
Uric acid	DMA1MKT	Investigative	Uric acid increases the expression of Ketohexokinase (KHK).	[13]

References

• [1] Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994 Sep;3(9):1627-31. doi: 10.1093/hmg/3.9.1627.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [13] Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J Biol Chem. 2019 Mar 15;294(11):4272-4281. doi: 10.1074/jbc.RA118.006158. Epub 2019 Jan 16.
• [14] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.